期刊
GASTROENTEROLOGY
卷 144, 期 7, 页码 1508-U328出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2013.02.003
关键词
Innate Immunity; Interferon-alpha; Antiviral; Pathogen Recognition; TLR-7
资金
- NCRR NIH HHS [P51 RR13986, C06 RR 12087, P51 RR013986] Funding Source: Medline
- NIH HHS [P51 OD011133, OD P51 OD011133] Funding Source: Medline
BACKGROUND & AIMS: Direct-acting antiviral agents suppress hepatitis B virus (HBV) load, but they require life-long use. Stimulation of the innate immune system could increase its ability to control the virus and have long-lasting effects after a finite regimen. We investigated the effects of immune activation with GS-9620-a potent and selective orally active small molecule agonist of Tolllike receptor 7-in chimpanzees with chronic HBV infection. METHODS: GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1-week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620. RESULTS: Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of > 1 log persisted for months. Serum levels of HBV surface antigen and HBV e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of interferon-alpha and other cytokines and chemokines, and activated interferon-stimulated genes, natural killer cells, and lymphocyte subsets. CONCLUSIONS: The small molecule GS-9620 activates Toll-like receptor 7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.
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